title: NSC126188 induces apoptosis of prostate cancer PC-3 cells through inhibition of Akt membrane translocation, FoxO3a activation, and RhoB transcription.
abstract: We previously reported that NSC126188 caused apoptosis of cancer cells by inducing expression of RhoB. We here present that NSC126188 induces apoptosis of prostate cancer PC-3 cells by inhibiting Akt/FoxO3 signaling, which mediates RhoB upregulation. The apoptosis and Akt dephosphorylation caused by NSC126188 was not substantially relieved by overexpressing wild-type Akt but was relieved by overexpressing constitutively active Akt (CA-Akt) or myristoylated Akt (myr-Akt). Furthermore, overexpression of CA-Akt or myr-Akt downregulated RhoB expression, indicating that RhoB expression is regulated by Akt signaling. Interestingly, membrane translocation of GFP-Akt by insulin exposure was abolished in the cells pretreated with NSC126188 suggesting that NSC126188 directly interfered with translocation of Akt to the plasma membrane. In addition, NSC126188 activated FoxO3a by dephosphorylating S253 via Akt inhibition. Activated FoxO3a translocated to the nucleus and increased transcription of RhoB and other target genes. PC-3 cells transiently overexpressing FoxO3a exhibited increased RhoB expression and apoptosis in response to NSC126188. Conversely, FoxO3a knockdown reduced NSC126188-induced RhoB expression and cell death. These results suggest that RhoB may be a target gene of FoxO3a and is regulated by Akt signaling. Taken together, NSC126188 induces apoptosis of PC-3 cells by interfering with membrane recruitment of Akt, resulting in Akt dephosphorylation and FoxO3a activation, which leads to transcription of RhoB.
authors.affiliation: Medical Genome Research Center, KRIBB, Taejon, 305-806, Korea.
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.forename: Bo Kyung
authors.initials: BK
authors.lastname: Kim
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Jung
authors.forename: Hwan-Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Kyung Bin
authors.initials: KB
authors.lastname: Song
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Chung
authors.forename: Misun
authors.initials: M
authors.lastname: Won
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D020743:rhoB GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C558305:4-hexadecanoyl-1,1-dimethylpiperazin-1-ium; D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010879:Piperazines; D051057:Proto-Oncogene Proteins c-akt; D020743:rhoB GTP-Binding Protein